Phenyl styryl ketone thiosemicarbazones



United States Patent STYRYL'KET ONE THIOSEMI- -CARBAZONES Hans Schmidt, Wuppertal-Vohwinkel, Robert Behnisch,

Wuppertal-Spnnborn, and Ernst Schraufstatter, -Wuppertal-Elberfeld, Germany, assignors to Schenley Industries, Inc., New York, N. Y., a corporation of Delaware No Drawing. Application February 18, 1954, Serial No. 411,264

Claims priority, applicationGermany July 6, 1950 3 Claims. (Cl. Z60552) The present invention relates to novel organic chemical compounds of a chemotherapeutic nature. More particularly, the invention contemplatestheprovision of a novel group of phenyl styryl ketone thiosemicarbazones which, preferably, have one or more substituents on the benzene nucleus of the styryl moiety, and which are characterized by their antiarthritic activity.

This application is a continuation-in-part of our copending U. S. application'SerialNo. 235,391 filed July 5, 1951, entitled Chemical Compounds and Process For Preparing the Same (now abandoned).

Heretofore, various aromatic thiosemicarbazones have been investigated and. tested in the treatment of arthritis such as reported by Heilmeyer in Verhandlungen der Deutschen Gesellschaft fiir Innere Medizin, 195l, page 463, The cortisone-like Action of Thiosemicarbazones,

and by Kuhlman, ibid. page 469, The Endocrine Mechanism of Action of the Thiosemicarbazones on Chronic Arthritis. As a result of these investigations and other investigations conducted with known compounds of the thiosemicarbazone series for determining their efficacy against pathogenic microorganisms that cause tuberculosis, it has been found that the aldehyde thiosemicarbazones have the strongest inhibitory efiect, Whereas the ketone thiosemicarbazones have been found, in general, to be less effective or even ineffectiveand essentially more toxic than the aldehydesubstituted compounds ofthe general class described.

We have found that the. specific class of novelketone thiosemicarbazones herein described constitute an excepe tion to the aforementioned findings of prior investigators, in that, these compounds are high:eifective against arthritis. This new class of compounds consists-of the thiosemicarbazones of phenyl styryl ketones which may have one or more therapeutically activating substituents on the benzene nucleus of the styrylmoiety, as for example, substituents such as halogen, alkanoylamino, alkylamino, alkoxy, aryloxy, acyloxy, nitro, carboxy, carboxyalkoxy and alkylsulfonyl groups. The benzene nucleus of the styryl moiety may bear one or more of these substituents, A

wherein R and R are members ofthe groupconsist-ing of'hydrogen, methyl, phenoxy, short-chain alkoxy com- 60 This new class of compounds may be represented by H r 2,768,970 Patented Oct. 30, 1956 "ice 2 methylamino, acetylamino, nitro, acetoxy, ethylsulfonyl (C2H5SO2), carboxy, 'carboxyvinyl and carboxymethoxy groups and R is a member of the group consisting of methyl, methylmercapto, methoxy, h'alogen'and carboxy groups and hydrogen.

The compounds of this class may be prepared following the procedure generally employed for producing thiosemicarbazones as by reacting thiosemicarbazide upon the selected ketone. Catalysts may be employed if necessary. Also, the substituentgroups may be exchanged, for other substituent groups on preformed thiosemicarbazones'by known methods. 7

In orderto facilitate a better understanding'of this invention, the'following examples are provided illustrating the manner of producing a number of representative thiosemicarbazones of the class. Itis to be understood that these examples are not intended to imp ose any limi-' cations on the invention, except as defined in the claims.

Example 1 Preparation, of the compound represented by the formula:

Example -2 The preparation of thecompound represented by the' formula:

HsC O Approximately:l2. grams .of .-4 1' methoXy-henzalac'tophenone and 4.5 grams of thiosemicarbazideare boiled in 500 cc. of ethyl.:alcohol for l2- hours,-then 100 cc. of

' Water are added. The solution is filtered off and allowed prising at most 4 carbon atoms, allyloxy, halogen, -dito crystallize, yielding the product 4-metho y-benzalacetophenone thiosemicarbazone, which, after being recrystallized from ethyl alcohol, melts at 142 C.

By recrystalliziug from glacial acetic acid an isomer is recovered having a melt-in'g point of C.

Example 3 Preparation of the compound represented by the formula:

on= oH- :=N.NH.c 1s .NH, 0.11.0

12.6 grams of 4-ethoxychalcone and 4.5 grams of thiosemicarbazide are refluxed for 48 hours in 500 cc. of ethanol. The alcohol is then evaporated, the residue boiled with ligroin and recrystallized from aqueous ethanol (20:80). The ethoxybenzalacetophenone thiosemicarbazone thus obtained melts at 157 C. The samecompound is obtained by boiling 25.2 grams of 4rethoxychalcone and 9.1 grams of thiosemicarbazide in a mixture of 50 cc. of glacial acetic acid and 50 cc. of ethanol for two hours.

' In the same manner we obtained: 4-n-propoxybenzalacetophenone thiosemicarbazone (melting point 164 C.) from 4-n-propoxybenzalacetophenone (melting point 59 C.). This compound is represented by the formula:

In like manner 4-allyloxybenzalacetophenone thiosemicarbazone (melting point 159 C.) from 4-allyloxybenzalacetophenone (melting point 66 C.), a compound represented by the formula:

4-n-butoxybenzalacetophenone thiosemicarbazone (melting point 150 C.) from 4-n-butoxybenzalacetophenone (melting point 64 C.), a compound represented by the formula:

(VII) and 4-phenoxybenzalacetophenone thiosemicarbazone (melting point 171 C.) from 4-phenoxybenzalacetophenone (melting point 94 C.), a compound represented by the formula:

Example 4 Preparation of a compound represented by the formula:

12 grams of 3-methoxybenzalacetophenone and 4.5

(VIII) OCH and

Example 5 Preparation of the compound represented by the formula:

OCH; (XII) 13.4 grams of 4:4-dimethoxybenzalacetophenone were refluxed for 48 hours with 4.5 grams of thiosemicarbazide in 500 cc. of ethanol. After distilling off the alcohol the residue was boiled with ligroin and then with water. It was recrystallized from ethanol. The 4:4-dimethoxybenzalacetone thiosemicarbazone melts at C.

In the same manner, by replacing the 4:4'-dimethoxybenzalacetophenone with 4'-methoxybenzalacetone, the product obtained is 4-methoxybenzalacetone thiosemicarbazone (melting point 286 C.), a compound represented by the formula:

by replacing the 4:4-dimethoxybenzalacetophenone with 4-methoxy-4-methylbenzalacetophenone, the product obtained is 4-methoxy-4'-methylbenzalacetophenone thiosemicarbazone (melting point 199 C.), a compound represented by the formula:

CH=CH(F=N.NH.C (:S).NH1 11.00 Q

Ha (XIV) and, by replacing the 4:4'-dimethoxybenzalacetophenone with 4-methoxy-4'-chlorobenzalacetophenone, the product obtained 4-methoxy-4'-chlorobenzalacetone thio- .E" semiearsaz'one(mauaapeim zw cieeia baaa ree resented by the formula: r

on on-( emulate 1s .NH,

. p .3 i .(XV)

Pre ara'tion of the 'co'm'p'ouncl "represented by the formula:

aHsO '-J H.-- (XVI) 13.3 grams of 4-ethoxy l methylbenzalacetophenone (melting point '99 7 C. .obtained .from 4.-methyl acetophenone and '4-ethoxybenzaldhyde) and 4.5 grams of thiosemicarbazide were refiuxedfor 48 hours in 500 cc. of ethanol. The alcohol is distilled ofi, the residue boiled with ligroin and recrystallized'from alcohol/water 80:20. The 4-ethoxy-4-methylbenzalacetophenone thiosemicarbazone recovered melts at 155 C.

Example 7 Preparation of a compound represented'vby the formula:

w, (XVII) 13.3 grams of "acetoxybenzalac'etophenone and 4.5 grams of thiosemicarbazide were refluxed for 48 hours in 500 cc. of ethanol. The reaction mixture is poured into Water; "the ipr ecipitatev separated by *suction "filtration, dried, and boiled Withligroin. ,The residue is recrystallized from aqueous alcohol :80. The 4-acetoxybenzal- Example 10 Preparation of a compound represented by the formula:

OzN

12.6 grams of 4-nitrobenzalacetophenone and 4.5 grams se c rbazide a e-re xed fe 2 1 inVQOCC- of ethanol. 300 cc. of water are added and the mixture left to crystallize, The crystals are boiled with benzene and then with Water. The residue is recrystallized from ethanol and then has the 'melting point C. It is 4-nitrobenzalacetophenone thiosemicarbazone.

Example 11 7 Preparation of a compound represented by the formula:

(XXI) About 18.3 grams of 3:5-dibromobenzalacetophenone (melting at 133 C., which maybe prepared by reacting 3:5-dibromo-benzaldehyde with acetophenone in an alcoholic alkali solution) and 4.5- grams of thiosemicarbazide are boiled under reflux in 500 cc. of ethyl alcohol for 48 hours. After distilling off the ethyl. alcohol, unreacted starting material is removed with boiling ligroin and the residue of 3 :5 -dibromo-benzalacetophenone'thiosemicarbazone is recrystallized from alcohol. The product thus obtained melts at 227 C.

In the same manner, by replacing the 3:5-dibromobenzalacetophenone with '4-'chlorobenzalacetophenone, the product obtained is -4-cholorbenzalacetophenone'thiosemicarbazone (melting-point 164" C.), va compound represented by the formula:

and by replacing the 3:5-dimethoxybenzalacetophenone with 4'-methoxy -4'-bromobenzalacetophenone,-the product obtained is 4-methoxy-4'-bromobenzalacetophenone thiosemicarbazone (melting point 223 C., a compound represented bythe formula:

7 Example 12 Preparation of a compound represented by the formula:

CzHsSOz (XXIV) Approximately grams of 4-ethylsulfonyl-benzalacetophenone (melting at 145 C., which may be prepared by reacting 4-ethylsulfonyl-benzaldehyde with acetophenone in an alcoholic alkali solution) and 4.5 grams of thiosemicarbazide are boiled in 500 cc. of ethyl alcohol for 12 hours. The thiosemicarbazone of 4-ethylsulfonyl-benzalacetophenone which precipitates is filtered off and recrystallized from ethyl alcohol, yielding a product which melts at 211 C. with decomposition.

Example 13 Preparation of a compound represented by the formula:

HgCO

S CHs (XXV) 14.2 grams of 4-methoxy-4'-methylmercaptobenzalacetophenone (melting point 132 C., obtained from 4- methylmercaptoacetophcnone and 4-methoxybenzalde hyde) and 4.5 grams of thiosemicarbazide are refluxed for 72 hours in 500 cc. of ethanol. After distilling off the alcohol, the residue is extracted with a little benzene and recrystallized from aqueous ethanol :80. The resulting 4-methoXy-4'-methylmercaptobenzalacetone-thiosemicarbazone melts at 155 C.

Example 14 Preparation of a compound represented by the formula:

About 12.6 grams of 4-carboxybenzalacetophenone (melting point 227 C., which may be prepared by reacting benzaldehyde-4-carboxylic acid with acetophenone in a 10% caustic soda solution) and 4.5 grams of thiosemicarbazide are refluxed in 500 cc. of ethyl alcohol for 48 hours. The thiosemicarbazone of 4-carboxybenzalacetophenone precipitates as yellow crystals which decompose when heated at 253 C. This product can be easily dissolved in aqueous mixtures containing alkanolamines, for instance, diethanolamine, with the formation of the alkanolamine (e. g. diethanolamine) salts.

In the same manner we obtained:

4-carboxy-4'-chlorobenzalacetophenone thiosemicarba-' zone (melting point 263 C.), a compound represented by the formula:

(XX V I) (XXVII) from 4-carboxy-4'-chlorobenzalacetophenone (melting point 267 C.);

4' carboxybenzalacetophenone thiosemicarbazone (melting point 224 C.), a compound represented by the G 0:11 (XXVIII) from 4'-carboxybenzalacetophenone, and 4-methoxy-4- carboxybenzalacetophenone thiosemicarbazone (melting point 224 C.), a compound represented by the formula:

C 01H from 4-methoxy-4-carboxybenzalacetophenone.

(XXIX) Example 15 Preparation of a compound represented by the formula:

OH=C HC=N.NH.C (:8) .NH,

(5H ll OH.C OaH (XXX) 14 grams of benzalacetophenone-4-p-acrylic acid (melting point 250 C. with decomposition, obtained from 4-formy1cinnamic acid and acetophenone in 10 percent sodium hydroxide solution) and 4.5 grams of thiosemicarbazide are heated for 96 hours in 500 cc. of ethanol. The thiosemicarbazone of benzalacetophenone- (4.p)-acrylic acid precipitates. It melts with decomposition at 258 C.

Example 16 Preparation of a compound represented by the formula:

oH=0HG=N.NH.o(:s).NH,

( CH CODH (XXXI) phenone (melting point 137 C.) yields a thiosemicarbazone, which, after being recrystallized from ethanol/ water 60:40, melts at 181 C. with decomposition. This product is a compound represented by the formula:

011100011 Representative members of the class of phenyl styryl ketone thiosemicarbazones have been extensively tested for their antiarthritic activity in controlled animal tests. Clinical trials have also been made on representative members of the class such as 4--ethoXy-benzaldehyde-acetophenone thiosemicarbazone, in which these compounds have proven to be effective in combating arthritis.

In some of the animal tests, using rats as the test animals, the antiarthritic effectiveness of the new thiosemicarbazones has been compared with that of anisalacetone thiosernicarbazone. Two representative compounds of F. Frey and R. Fischer, Archiv filr Experimentell Pathologie und Pharmakologie 213 z 387, (1951). (c) Tests for eifectiveness against arthritic stress .induced by subplantary administration of formaldehyde and termed for identification Selye Arthritis. The average reaction of groups of at least five animals was evaluation. The procedure of at least the recommendations of Selye in The British Medical Journal (1949): 1129.

The results of these three groups of tests are summathe new class were selected for this comparison these 10 rized in the following table:

Eosinophile Lymphocyte Selye Protein Quotient Quotient Arthritis Arthritis (1) 4-methoxybenzalacetophenone good 5.1 very good 2.2.. good effect no test.

thiosemicarbazone. (2) 4-acetoxybenzalaeetophenone very good 8.3 poor 1.0 do moderate thiosemiearbazone. etfect. (3) 4-allyloxybenzalacetophenone good 5.4 good 1.7 do very good efthiosemicarbazone. feet. (4) 4-n-propoxybenzalacetophenone good 5.7 very good 1.9 good effect.

thiosernicarbazone. (5) 4-ethoxybenzalacetophenone very good 7.6. very good 2.1.. very good eithiosemiearbazone. feet. (6) 3-111ethoxybenzalacetopheuone good 4.8 good 1.6 good no test.

thiosemicarbazone. (7) 3,4-dimethoxybenzalactophenone very good 10.1. good 1.6 do Do.

thiosemicarbazone.

Compound Eosinophtls Lymphocytes anisalacetone thiosemicarbazone 1.0 1.0 -methoxybenzalacetophenone thiosemicarbazone 4. 0 2. 1 4-ethoxybenzalaeetophenone thiosemioarbazone 8.1 2.3

In further more extensive animal tests also using rats as the test animals a number of the new compounds were tested and evaluated for their effectiveness on the basis of the effect of cortisone in identical tests. These tests were divided into three sections: (a) Tests for Eosinophile quotient and Lymphocyte quotient following an experimental procedure approximating that of A. E. Heming et al. (Journal of Pathology and Experimental Therapeutics 106 271, 1952). Here it may be noted that the activity of the compound becomes interesting when the activity quotient of the eosinophils is higher than 4 and that of the lymphocytes is higher than 1.5. (b) Tests for effectiveness against arthritic stress induced by injection of undiluted chicken egg white and termed for identification Protein Arthritis. A group of at least five animals was used for average evaluation of each preparation, the procedure used being that of L. Heilmeyer,

Having thus described the subject matter of the inven tion with reference to specific examples, what is desired to secure by Letters Patent is:

1. A chemotherapeutic compound represented by the formula:

wherein R is a member of the group consisting of hydrogen, and short chain alkyl radicals containing at most four (4) carbon atoms.

2. A chemotherapeutic compound as claimed is claim 1 wherein R is methyl.

3. A chemotherapeutic compound as claimed in claim 1 wherein R is ethyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,676,978 Schmidt et al Apr. 27, 1954 2,683,171 Schmidt et al. July 6, 1954 FOREIGN PATENTS 584,371 Great Britain J an. 14, 1947 OTHER REFERENCES Sah eta1.: Rec. Trav. Chim., vol. 69 (1950), pp. 1554, 1547. 

1. A CHEMOTHERAPEUTIC COMPOUND REPRESENTED BY THE FORMULA: 